Injury to the spinal cord or the central nervous system in general initiates a cascade of complex events, the net effect of which is a limiting neurological deficit. The magnitude of the deficit is determined not only by the extent of the initial injury but also, by variation within the events that follow. Many studies point to the realization that in order to understand these events, and perhaps devise strategies that can improve the likelihood of a more favorable neurological outcome, we must first understand the fundamental cellular mechanisms influencing degenerative and regenerative events within the CNS. The ultimate goal of the projects described in this program proposal is to develop a body of knowledge that will help us to identify basic mechanisms that may be susceptible to intervention strategies that would improve outcome following injury. The program is divided into 6 major areas: 1) A Core facility providing support for electron microscopy and administration; 2) Studies designed to test specific hypotheses about postsynaptic mechanisms that influence the response to injury; 3) The influence of trophic mechanisms including specific membrane bound proteins on attempts at regeneration; 4) Studies on the role of intrinsic local circuits and descending circuits in the development of post-injury abnormal sensory responses; 5) Experiments designed to explore the effects of injury on membrane mechanisms of excitability such as voltage-gated channels; and 6) Experiments designed to test the hypothesis that the placement of an axotomy is an important determinant in the subsequent response of the neuron. Pursuing these studies will fill critical gaps in our current understanding of degenerative/regenerative processes occurring within the central nervous system. This knowledge is essential for the development of treatment strategies directed not only at the spinal cord but the central nervous system in general.